Despite much progress, cardiovascular diseases (CVD), which include hypertension, coronary heart disease (CHD), ischemic cerebrovascular disease (strokes) and peripheral vascular disease, remain among the leading causes of mortality and morbidity of adults in the USA and other developed countries. The introduction of highly-effective cholesterol-lowering drugs (statins) have clearly demonstrated a causative relationship between hypercholesterolemia and CHD. Despite the enormous medical success of stain therapy, a significant number of patients suffer toxicity, requiring cessation of drug administration. We propose to develop the recently discover RNA interference technology to treat hypercholesterolemia. We will also explore intervention at other junctures in the lipid metabolism pathway. Double stranded RNA was found to strongly inhibit gene expression in a sequence-specific manner. Application of small (21-25 bp) interfering RNA (siRNA) is equally effective, specific, and avoids the induction of non-specific effects (e.g., interferon induction). We have recently demonstrated that siRNA can be efficiently introduced in liver cells in vivo, and used to modulate gene expression. In this SBIR Phase I grant proposal, we will use our intravascular in vivo delivery methods to characterize the siRNA activity profile and explore the possibilities to use siRNA for the treatment of hyperlipidemias. These experiments should demonstrate the feasibility of using siRNA for therapeutic purposes and in other application such as target validation. In the accompanying Phase II application, we propose to develop efficient siRNA delivery systems, based on Mirus DNA particle (artificial virus) technologies.